Development of a Vaccine Against Human Cytomegalovirus: Advances, Barriers, and Implications for the Clinical Practice
Total Page：16
File Type：pdf, Size：1020Kb
Review Development of a Vaccine against Human Cytomegalovirus: Advances, Barriers, and Implications for the Clinical Practice Sara Scarpini 1, Francesca Morigi 1, Ludovica Betti 1, Arianna Dondi 2,* , Carlotta Biagi 2 and Marcello Lanari 2 1 Specialty School of Pediatrics, Alma Mater Studiorum, University of Bologna, 40126 Bologna, Italy; [email protected] (S.S.); [email protected] (F.M.); [email protected] (L.B.) 2 Pediatric Emergency Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; [email protected] (C.B.); [email protected] (M.L.) * Correspondence: [email protected] Abstract: Human cytomegalovirus (hCMV) is one of the most common causes of congenital infection in the post-rubella era, representing a major public health concern. Although most cases are asymp- tomatic in the neonatal period, congenital CMV (cCMV) disease can result in permanent impairment of cognitive development and represents the leading cause of non-genetic sensorineural hearing loss. Moreover, even if hCMV mostly causes asymptomatic or pauci-symptomatic infections in immunocompetent hosts, it may lead to severe and life-threatening disease in immunocompromised patients. Since immunity reduces the severity of disease, in the last years, the development of an effective and safe hCMV vaccine has been of great interest to pharmacologic researchers. Both hCMV live vaccines—e.g., live-attenuated, chimeric, viral-based—and non-living ones—subunit, RNA-based, virus-like particles, plasmid-based DNA—have been investigated. Encouraging data are emerging from clinical trials, but a hCMV vaccine has not been licensed yet. Major difficulties in Citation: Scarpini, S.; Morigi, F.; the development of a satisfactory vaccine include hCMV’s capacity to evade the immune response, Betti, L.; Dondi, A.; Biagi, C.; Lanari, M. Development of a Vaccine against unclear immune correlates for protection, low number of available animal models, and insufficient Human Cytomegalovirus: Advances, general awareness. Moreover, there is a need to determine which may be the best target populations Barriers, and Implications for the for vaccine administration. The aim of the present paper is to examine the status of hCMV vaccines Clinical Practice. Vaccines 2021, 9, 551. undergoing clinical trials and understand barriers limiting their development. https://doi.org/10.3390/ vaccines9060551 Keywords: hCMV; vaccine; mRNA vaccines; congenital CMV; congenital infection; prevention; CMV long-term sequelae; sensorineural hearing loss Academic Editor: Ralph A. Tripp Received: 29 April 2021 Accepted: 22 May 2021 1. Introduction Published: 25 May 2021 1.1. Epidemiology Publisher’s Note: MDPI stays neutral Human cytomegalovirus (hCMV), which is one of the eight herpesviruses known with regard to jurisdictional claims in to infect humans, is widespread all around the world and is mostly asymptomatic in published maps and institutional affil- immunocompetent people [1]. However, hCMV may lead to severe and life-threatening iations. disease in congenitally infected children and immunosuppressed individuals, such as transplant patients and those affected by acquired immunodeficiency syndrome (AIDS) [2]. hCMV is the most frequent cause of vertical transmission infections. The rate of con- genital hCMV (cCMV) transmission is between 0.5% and 0.7% of pregnancies in developed nations, and up to 2% of pregnancies in the developing world [3]. The major sources of the Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. virus for expectant mothers are young children with hCMV, most of all toddlers, who can This article is an open access article produce saliva and urine with high levels of hCMV [4]. Intrauterine hCMV transmission distributed under the terms and may occur in mothers without pre-existing antibodies who acquire a primary hCMV infec- conditions of the Creative Commons tion during pregnancy but also in women who have had previous contacts with hCMV Attribution (CC BY) license (https:// (non-primary infection). In the context of primary infection, 1–4% of seronegative women creativecommons.org/licenses/by/ seroconverted during pregnancy, but the symptoms, when present, are often too mild to 4.0/). seek medical attention. Thus, if hCMV is not tested during pregnancy, the infection is Vaccines 2021, 9, 551. https://doi.org/10.3390/vaccines9060551 https://www.mdpi.com/journal/vaccines Vaccines 2021, 9, 551 2 of 26 usually not recognized [5,6]. In primary infection, hCMV is transmitted across the placenta in up to 30–50% of the cases, producing fetal infection [5]. Non-primary infection occurs when the fetus is infected because of viral reactivation or in case of maternal reinfection with a different hCMV strain [7]. In such circumstances, the likelihood of hCMV transmis- sion to the fetus is in the range of approximately 3% [5]. However, about three-quarters of cCMV infections are caused by non-primary maternal infection, given the high rates of hCMV seropositivity among women of childbearing age [8]. Vertical transmission is more frequent in mothers with older gestational age, while the risk of fetal damage is higher when infection occurs in the early stages of pregnancy [9,10]. hCMV morbidity and mortality can also occur in immunosuppressed people, mostly AIDS or transplant patients, in whom the virus often behaves like an opportunistic pathogen [11,12]. Before the development of antiretroviral therapy, up to 40% of AIDS patients had severe hCMV disease, often sight-threatening [12], while the introduction of such therapy has led to a rapid decline in the incidence of hCMV manifestations and a better prognosis of patients with hCMV disease [13]. In parallel, hCMV infection represents a frequent complication in the setting of hematopoietic stem cell transplantation (HSCT) and solid organ transplantation (SOT) [11], possibly leading to graft rejection. In the case of SOT, when a hCMV seronegative recipient receives an organ from a seropositive donor, the disease develops in more than 50% of cases if no pre-emptive prophylaxis is given [14]. However, even seropositive recipients may have hCMV disease, given the possibility of superinfection with a new strain or reactivation, even if the latter case is less frequent [15]. Differently, after HSCT, the most frequent cause of disease is hCMV reactivation under the influence of immunosuppression in a seropositive recipient [16]. Antiviral prophylaxis, or treatment when needed, is administered routinely to SOT and HSCT patients to prevent serious disease and is significantly but not completely successful [17]. Finally, hCMV may also pose a danger to intensive care unit (ICU) patients, since it has been demonstrated that it is associated with an increased risk of all-cause mortality, increased hospital and ICU length of stay, longer duration of mechanical ventilation, and increased rates of nosocomial infection [18]. 1.2. Virology hCMV is a member of the Betaherpesvirinae sub-family of Herpesviridae [19]. It has an icosahedral capsid that contains the double-stranded DNA, encoding for 165 proteins. As shown in Figure1, the capsid is surrounded by a tegument made of proteins and, externally, by a lipid envelope [19], whose glycoproteins allow the entry into the host cells through fusion with the cell membrane. After fusion, the viral capsid with the DNA and the tegument proteins are released into the cell [20]. The virus contains various distinct types of glycoprotein complexes (gC) that are useful to infect the host [21]: gC-I is a complex composed of homotrimers of glycoprotein B (gB), a pan-Herpesviridae conserved glycoprotein, mediator of membrane fusion, that rearranges during entry into the cell from a pre-fusion conformation to a post-fusion one; gC-II is the most abundant gC, is made up of glycoprotein M (gM) and N (gN), contributes to the initial binding to the cell membrane, and plays a role in viral replication; gC-III, now called trimer complex (TC), is a heterotrimeric complex where glycoprotein H (gH), L (gL), and O (gO) are linked together, with gH and gL being involved in activating the fusogenic activity of gB, and gO working as a co-receptor. Since its discovery in the middle of the last century, hCMV has been cultivated in fibroblast cell cultures [22]. The discovery of hCMV variants that were no longer able to infect leukocytes and endothelial cells happened at the beginning of the 2000s, leading to the hypothesis that a mutation occurred in laboratory-cultivated strains. This was the starting point of the studies about genetic determinants of hCMV cell tropism [22]. A study carried out by Italian and German researchers in 2002 highlighted the role of the UL128, UL130, and UL131 locus of the hCMV genome in virus growth in endothelial cells and virus transfer to leukocytes [23]. Wang et al. [24] documented the presence of another protein complex, composed of gH/gL combined with UL128, UL130, and UL131 proteins Vaccines 2021, 9, x 3 of 27 Vaccines 2021, 9, 551 3 of 26 cells and virus transfer to leukocytes [23]. Wang et al. [24] documented the presence of another protein complex, composed of gH/gL combined with UL128, UL130, and UL131 proteins (pUL128–pUL131), different from TC, required to infect epithelial and endothe- (pUL128–pUL131), different from TC, required to infect epithelial and endothelial cells; lial cells; they also found that antibodies to either protein of this pentameric structure neu- they also found that antibodies to either protein of this pentameric structure neutralized tralized the ability of hCMV to infect endothelial and epithelial cells but not fibroblasts. the ability of hCMV to infect endothelial and epithelial cells but not fibroblasts. Another Another study showed that hCMV enters epithelial and endothelial cells by endocytosis study showed that hCMV enters epithelial and endothelial cells by endocytosis followed by followed by low-pH-dependent fusion, which is different from the pH-independent fu- low-pH-dependent fusion, which is different from the pH-independent fusion with human fibroblastssion with human [25]. The fibroblasts mechanism [25].